Pharmacotherapy of amphetamine-type stimulant - PowerPoint Presentation

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Pharmacotherapy of amphetamine-type stimulant dependence

Stimulants seminar shahid sadoughi university of medical sciencesEsfand 1393M Yassini MD

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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refrences

Drug and Alcohol Review (September 2013), 32, 449–460 Comprehensive textbook of psychiatry2009 Kaplan and sadockNeurobiology of Addiction Koob, Michel Le MoalSynopsis of psychiatry 2015

Kaplan and sadock

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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objectivesThis

review describes the rationale and targets for pharmacotherapies for abuse or dependence on ATS reviews the extant evidence for select agentsdiscusses emerging

pharmacogenetic dataproposes

directions for future work

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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underlying mechanisms for pharmacotherapy

alter the neurobiology of reinforcement or reward from the drugattenuate the negative reinforcing effects of withdrawal from and craving for the drug

Ameliorate comorbid psychiatric vulnerabilities that co-occur and that can interfere with recovery.

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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Methamphetamineeffect

increases extracellular levels of monoamines both byblocking presynaptic reuptake Stimulating the release of

catecholamines through the disruption of vesicular storage

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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Rewarding effect of methamphetamine

mediated by neurotransmitter systems including dopamine, serotonin and norepinephrine dopaminergic system a favoured

target for pharmacotherapy

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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neuroadaptationsInitial positive

and rewarding subjective effects of methamphetamine dull in quality with repeated use of the drug, signalling development of a series of neuroadaptationsM Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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neuroadaptations

Koob and Le Moal [16] characterise this process as the increasing recruitment of anti-reward processes, including- hypoactivity in the dopaminergic system-

alterations in hypothalamic–pituitary–adrenal axis functioning

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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Evaluated medications

AgonistsantagonistsM Yassini MD.yazd medical sciences university. yassiniard@yahoo.com11Slide12

antagonistsblock

the action of the agonist to attenuate or eliminate the positive reinforcing effects of acute methamphetamine intoxication.compete with endogenous monoamines but have no intrinsic activity at the receptor siteNaltrexone in other addiction

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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agonists

bind to and trigger responses from receptors involved in the addiction process, often mimicking the action of monoamines involved in the reinforcement, withdrawal symptoms and motivational aspects of methamphetamine or amphetamine usepromote early abstinence by providing

a modest level of subjective effects but may have their greatest

impact in

minimizing

withdrawal and

negative affective

symptoms

.

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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Antagonists strategies

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Naltrexone

an opioid receptor antagonistopioid receptors partially modulate dopaminergic effects and may act as a relevant pharmacological target.encouraging but await confirmation in several clinical trials that are currently underway

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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mixed dopamine and serotonin antagonist

Risperidone in small samples of methamphetamine-dependent adults showed acceptability and decreases in weekly methamphetamine usequetiapine and risperidone equally reduced

bipolar symptoms and drug cravings, with reductions in cravings associating

with reductions in stimulant use

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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mixed dopamine and serotonin antagonist

However, in non-dependent volunteers in the human laboratory, neither haloperidol nor risperidone attenuated the euphorigenic effects of methamphetamine

dampening rationale for further evaluation

of dopamine

antagonists.

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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aripiperazoleiatrogenic

effectExacerbation of drug useAttenuate psychotic symptomsM Yassini MD.yazd medical sciences university. yassiniard@yahoo.com18Slide19

Agonist strategies

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Agonist therapies produce

behavioral and neurobiological effects that are comparable or identical with the drug of addictionM Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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Dexamphetamine

Increase extracellular levels of dopamine through a carrier mediated exchange at presynaptic vesicles. In a small unblinded

randomised trial, Shearer demonstrated initial

safety and feasibility

of dexamphetamine

replacement therapy

(60 mg/day) for injecting

amphetamine dependent individuals.

The

study was

underpowered

to detect

treatment differences

, but no serious

adverse events

were observed

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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methylphenidate

Additional support for an agonist approach is provided by Tiihonen 20-week, randomised, double-blind, placebo-controlled trial of aripiprazole, methylphenidate or placebo among participants dependent upon injection use of amphetamine

participants assigned to the 54 mg/day slow-release methylphenidate condition (n = 17) had significantly

fewer amphetamine-positive

urine samples than

placebo

treated

patients

(n = 19; odds ratio = 3.77; 95%

confidence interval

1.55, 9.18).

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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modafinile

nonamphetamine-type stimulant with wake-promoting properties and cognitive-enhancing effectsincreases dopamine availability in nucleus accumbensDespite disappointing findings, some enthusiasm still exists for modafinil

in its current form or one of its enantiomers, R-

modafinil

,

as a

treatment for

psychostimulant

dependence

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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Bupropion

Although not considered an agonist, bupropion functions as a mild stimulant and antidepressant.Bupropion is a non-selective inhibitor of the dopamine and norepinephrine transporters

also acts as an antagonist

at nicotinic acetylcholine

receptors

Bupropion increases dopamine transmission in

both the

nucleus

accumbens

and the prefrontal

cortex

encouraging but await confirmation

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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In sum

dopamine-enhancing medications have demonstrated the most consistent effects on reducing methamphetamine use when evaluated in placebo controlled randomized trials. One of the challenges t

o continued work using this strategy is that pure agonists have

abuse liability,

which elicits concerns that

limit impact

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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Serotonergic medications

marketed serotonin-specific reuptake inhibitors may be ineffective for treating methamphetamine dependence.compounds in development that have selective activity at specific

serotonergic receptors may be efficacious approaches. Indeed

,

one such

medication,

mirtazapine, has demonstrated

some promise

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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Mirtazapine

is a pharmacologically distinctive antidepressant with sedative and anxiolytic properties that enhances both noradrenergic and serotonergic activity.Its actions on the serotonergic system are different from those of selective serotonin reuptake inhibitors, including enhanced

transmission of 5-HT1A receptors and blockade of 5-HT2 and 5-HT3

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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GABAergic mechanisms

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GABA system

interacts with dopaminergic processes, and its activation exerts an inhibitory effect on the reward system.This feature suggests that GABA agents may have some efficacy in attenuating the

reinforcing effects of stimulants.

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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vigabatrine

Increases brain GABAAttenuate cocaine, nicotine, heroine, alcohol and amphetamine induced increases in extracellular nucleus accumbens dopamine as well as drug seeking behaviors associated with this biochemical changes in animals

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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GABAergic agents

Gabapentine has no effects on methamphetamine use, treatment retention or drug craving.topiramate appeared to facilitate abstinence during the second half of the trialBaclofen, tiagabine have shown some promise In preclinical studies and early clinical studies

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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Other agents

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Tricyclic antidepressants

Some positive results in early treatment with minimally drug dependent patientsLittle or no use inducing abstinence in moderate or severe casesDesipramine as most effective

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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dilantine

One study found 300mg a day of dilantine reduced cocaine use This study requires furthur replication M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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Cocaine vaccine

Cocaine binding antibodies Reduce the reinforcing effects of cocaine in animal modelsCatalytic antibodies Accelerate the hydrolysis of cocaineM Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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disulfiram

Inhibitor of dopamine beta dehydroxylate enzymeIncreases level of dopamine by slowing the breakdown of synaptic dopamineIncrease cocaine levels several foldCo administration of cocaine and disulfiram

make more negative response including anxiety, restlessness and paranoia so decreases cocaine use

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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conclusion

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com38Slide39

Complex disease

Numerous pharmacotherapies have been assessed in randomized, placebo-controlled trials but most have failed to demonstrate efficacyDependence on long-acting stimulants represent a complex disease of staged neuroplasticity

involving multiple brain systems

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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Optimal pharmacological targets

dopaminergic system—the principle focus in addiction medication research—is dependent on competent functioning of the GABA system and cholinergic interneuronsDetermining optimal pharmacological targets is

difficult

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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Agonist replacement therapies

Although the preponderance of findings from clinical trials have been negative, not all results have been disappointing.Agonist replacement therapies show some promise. Concerns, however, have been raised regarding public health implications of

widespread implementation of this strategy

.

Additionally

, agonist

therapies will

likely require significant

behavioural

support

and

oversight in order to deliver robust public

health benefits

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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bupropionNIDA has completed

a second, confirmatory trial of bupropion, and if results are similar to existing studies, support would exist for use of the medication as a pharmacotherapy.M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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novel mechanisms

Shoptaw and Heinzerling are assessing ibudilast, a phosphodiesterase inhibitor that may attenuate the cascade of methamphetamine-induced

glial activation and

release of cytokines

upon

initial abstinence

.

A

Phase I trial is being completed

Phase II trial of the compound

not finished

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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Mirtazapinedemonstrated

promise in a preliminary study being assessed in a larger trialM Yassini MD.yazd medical sciences university. yassiniard@yahoo.com44Slide45

Varenicline

a partial agonist at alpha-4, beta-2 nicotinic acetylcholine receptors is being examined as a pharmacotherapy following promising pilot data and encouraging results with both cocaine and alcoholevidence suggests involvement of the cholinergic system in the neurochemical effects of

methamphetamine use the reinstatement of methamphetamine MA-seeking in animal models

reduced

subjective effects of methamphetamine

in a

human laboratory study

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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N-acetylcysteine

Promising preclinical and human laboratory studies with cocaine have stimulated interest in N-acetylcysteine as a pharmacotherapy for methamphetamine dependence, though a Phase II trial is years away.

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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D3 receptor

NIDA has recently signalled an interest in a dopamine D3 receptor for cocaine dependence M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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buspironeTwo

randomized controlled trials will evaluate buspirone as a relapse prevention treatment among cocaine-dependent patients being discharged from inpatient treatment facilities

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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Final word

After over 20 years of concerted effort to develop a broadly effective medication for MA dependence, no candidate has emerged.This highlights the need for new research methodologies,

better integration between basic and clinical sciences and

improved

collaboration between

government, industry and

academic researchers

.

M Yassini MD.yazd medical sciences university. yassiniard@yahoo.com

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